The long-range goal of this research is to investigate the theoretical and potential practical implications of replacing the amide linkage of endogenous, physiologically active peptides with isosteric and/or isoelectronic functions not subject to enzymatic hydrolysis. For the purposes of this proposed initial study, we have selected the morphinoid penetapeptides, methionine- and leucine-enkephalin as attractive prototypes for investigation. We propose to: a) Synthesize analogs of the enkephalins in which one or more of the peptide N-H linkages is replaced by CH2; b) Synthesize analogs in which, in addition to replacement of N-H link(s) by CH2, modifications of the amino acid pendant groups are introduced, and other analogs in which the alpha-amino N of the tyrosine residue is substituted by 1-2 lower aliphatic groups; c) Evaluate the compounds for narcotic agonist and antagonist activities in vitro by the guinea pig ileum assay and in vivo by the mouse tail-flick test. Replacement of selected peptide N-H links by CH2 will permit us to probe: 1) requirements as to intramolecular hydrogen bonding and conformation for the enkephalins to bind to opioid receptors and to display opioid properties; and 2) possibilities for developing metabolically stable agents, showing useful durations of action, ideally after oral administration. Modification of the amino acid pendant groups and substitution of the tyrosine alpha-amino N will allow us to explore possibilities for enhancing pharmacologic potency and for modifying the balance of narcotic agonist to antagonist properties.